Bupropion is a safe and generally well-tolerated treatment for depression and nicotine dependence when used in doses <400mg/day. However, at higher doses, bupropion has an increased risk of seizure that may limit the ability of the drug to realize its maximum potential. Bupropion is extensively metabolized in man and in animals. The resulting hydroxybupropion (OHB) differs among man, rat and mouse. The metabolism is extensive with circulating OHB at 15-20 fold higher levels than parent bupropion. Application of chiral chromatography has determined that >95 percent of circulation OHB is the levorotatory enantiomer (-OHB). Studies, in-house, have demonstrated that -OHB is devoid of therapeutic activity but is 3-fold more toxic than +OHB. The present proposal is predicated on the hypothesis that formation of -OHB is enantioselective from (S)-bupropion and that the metabolism of (R)-bupropion, while much less acile, primarily results in +OHB. Studies, with human microsomes, are proposed to test this hypothesis. If successful, a Phase II submission will request support to conduct a proof-of-concept study in humans. PROPOSED COMMERCIAL APPLICATION: NOT AVAILABLE